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Impact of IKZF1 deletions and PAX5 amplifications in pediatric B-cell precursor ALL treated according to NOPHO protocols

Leukemia volume 27, pages 1936–1939 (2013)Cite this article

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Survival rates for childhood acute lymphoblastic leukemia (ALL) have increased dramatically over the last four decades due to a combination of intensified treatment, improved supportive care and risk stratifications based on several parameters including genetic aberrations. However, 10–20% of patients treated according to modern protocols still relapse and 10% do not survive the disease.1 Genetic lesions signaling high risk are rare and treatment failures occur across the whole spectrum of cytogenetic risk groups, while a substantial proportion of cases also lack characteristic rearrangements used for risk stratification.2

Deletion of the IKZF1 locus, coding for the lymphoid transcription factor IKAROS, has recently emerged as a potential prognostic marker in B-cell precursor ALL (BCP ALL).3 The vast majority of reported aberrations in IKZF1 are intragenic deletions, while sequencing of the IKZF1 gene has revealed a low frequency of point mutations.4, 5, 6, 7 Heterozygous deletions of the entire IKZF1 locus or individual exons are predicted to result in haploinsufficiency, whereas deletion of a specific subset of exons (Δ4-7) results in a shorter, dominant-negative isoform, IK6.8 Different isoforms of IKZF1, generated through alternative splicing, are expressed during normal B-cell development;9 however, several studies have demonstrated that expression of the IK6 isoform is pathogenic and caused by deletion only.10 Originally described as a characteristic of BCR-ABL1-positive ALL,8 IKZF1 deletions were later suggested to predict high relapse risk and poor prognosis in all types of BCP ALL.3 Moreover, these deletions have been associated with a gene expression profile resembling BCR-ABL1-positive ALL.11

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Acknowledgements

This study was supported by grants from the Swedish Childhood Cancer Foundation, Karolinska Institutet and Stockholm County Council.

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  1. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    I Öfverholm, A N Tran, V Zachariadis, M Nordenskjöld, A Nordgren & G Barbany

  2. Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

    M Heyman

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  1. I Öfverholm
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Correspondence to G Barbany.

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Öfverholm, I., Tran, A., Heyman, M. et al. Impact of IKZF1 deletions and PAX5 amplifications in pediatric B-cell precursor ALL treated according to NOPHO protocols. Leukemia 27, 1936–1939 (2013). https://doi.org/10.1038/leu.2013.92

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